chr6-30703749-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014641.3(MDC1):āc.5434A>Gā(p.Lys1812Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000905 in 1,547,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000086 ( 0 hom. )
Consequence
MDC1
NM_014641.3 missense
NM_014641.3 missense
Scores
6
12
Clinical Significance
Conservation
PhyloP100: 3.33
Genes affected
MDC1 (HGNC:21163): (mediator of DNA damage checkpoint 1) The protein encoded by this gene contains an N-terminal forkhead domain, two BRCA1 C-terminal (BRCT) motifs and a central domain with 13 repetitions of an approximately 41-amino acid sequence. The encoded protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. This nuclear protein interacts with phosphorylated histone H2AX near sites of DNA double-strand breaks through its BRCT motifs, and facilitates recruitment of the ATM kinase and meiotic recombination 11 protein complex to DNA damage foci. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14805222).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MDC1 | NM_014641.3 | c.5434A>G | p.Lys1812Glu | missense_variant | 10/15 | ENST00000376406.8 | |
MDC1-AS1 | NR_133647.1 | n.127+556T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MDC1 | ENST00000376406.8 | c.5434A>G | p.Lys1812Glu | missense_variant | 10/15 | 5 | NM_014641.3 | P1 | |
MDC1-AS1 | ENST00000442150.1 | n.127+556T>C | intron_variant, non_coding_transcript_variant | 3 | |||||
MDC1 | ENST00000489540.1 | n.333A>G | non_coding_transcript_exon_variant | 1/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000517 AC: 10AN: 193492Hom.: 0 AF XY: 0.0000488 AC XY: 5AN XY: 102356
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GnomAD4 exome AF: 0.00000860 AC: 12AN: 1395266Hom.: 0 Cov.: 33 AF XY: 0.00000872 AC XY: 6AN XY: 688212
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74474
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2022 | The c.5434A>G (p.K1812E) alteration is located in exon 10 (coding exon 9) of the MDC1 gene. This alteration results from a A to G substitution at nucleotide position 5434, causing the lysine (K) at amino acid position 1812 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at